Open AccessA High Prevalence of Functional Inactivation by Methylation Modification of p16 INK4A / CDKN2/MTS1 Gene in Primary Urothelial Cancers
Author(s) -
Akao Toshiya,
Kakehi Yoshiyuki,
Itoh Noriyuki,
Özdemir Enver,
Shimizu Takashi,
Tachibana Akira,
Sasaki Masao S.,
Yoshida Osamu
Publication year - 1997
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1997.tb00332.x
Subject(s) - epigenetics , biology , loss of heterozygosity , carcinogenesis , dna methylation , methylation , cpg site , cancer research , exon , microbiology and biotechnology , gene , mutation , tumor suppressor gene , gene expression , genetics , allele
We analyzed the genetic and epigenetic alterations p16 INK4A /CDKN2/MTSl gene (MTS1 gene) in 38 primary urothelial cancers. Genetic alterations of the MTS1 gene consisted of one base substitution mutation in exon 2(2.6%)and 6 homozygous deletions (16.2%). Hypermethylation of the 5’CpG island in exon 1 of the MTS1 genewas observed in 12 tumors (37.5%). Consequently, 19 of 38 tumors (50%) showed genetic alterations or epigenetic hypermethylation of the MTS1 gene. Retention of hypermethylated MTS1 gene(s) in 36% of the tumors showing loss of heterozygosity at the critical region indicates that the methylation modification could be an initial event followed by genomic rearrangements associated with total loss of MTS1 gene function. Immunohistochemical analysis of MTS1 expression revealed that all the tumors with genetic alterations of the MTS1 gene and 9 of 12 highly methylated tumors displayed an absence of MTS1 nuclear antigen. Genetic and epigenetic changes of theMTS1 gene were not correlated with the grade and stage of tumors, indicating that these alterations are early events in nrothelial carcinogenesis, in which functional inactivation by hypermethylation is a predominant mechanism.